Polypeptide Hormone Gene Regulation 
DNA-binding proteins and with adjacent target 
DNA sequences appear to determine cellular 
specificity of gene expression as well as metaboli- 
cally regulated expression. Recently we have 
cloned several members of a family of cAMP- 
responsive enhancer-binding proteins (CREBs) 
and have discovered a domain on one of the 
CREBs that is phosphorylated by the cAMP- 
dependent protein kinase A, as well as by addi- 
tional protein kinases. The phosphorylation of 
CREB has a profound effect of increasing the tran- 
sactivation of gene transcription. 
Discovery of an Insulinotropic Peptide 
We have discovered a new glucagon-like pep- 
tide related in its structure to pancreatic gluca- 
gon and co-encoded with glucagon in the precur- 
sor protein of the two hormones (proglucagon) . 
These peptides are differentially cleaved from 
the proglucagon, the initial translation product, 
in the pancreas and the intestines. One of the 
peptides, glucagon-like peptide ! (7-37) pro- 
duced in the intestine and released in response to 
oral nutrients has potent insulinotropic activi- 
ties. Concentrations as low as 10""- 10"'^ M 
stimulate insulin secretion in the perfused rat 
pancreas and stimulate both cAMP formation and 
proinsulin gene transcription and mRNA levels in 
insulinoma cell lines. We have determined that 
the glucagon-like peptide regulates insulin se- 
cretion in humans and propose that it may be in- 
volved in the pathogenesis of certain types of dia- 
betes mellitus due to a faulty regulation. 
Particular emphasis is on analyses of the |8-cell 
receptor for the glucagon-like peptide and the 
mechanisms operative in the stimulation of insu- 
lin gene transcription in response to the actions 
of the peptide. 
Our goals are 1) to characterize further the 
genes encoding the regulatory (DNA-binding) 
proteins that interact with tissue-specific en- 
hancers and to determine how cAMP-mediated 
expression of the peptide hormone-encoding 
genes is regulated in the specific cellular pheno- 
types and 2) to test further the new glucagon-like 
peptides for their potential regulatory actions 
within the pancreatic islets and the intestinal 
tract and to explore the possible role of the pep- 
tides in diabetes mellitus. 
Some of these studies were also supported by 
funds from the National Institutes of Health. 
176 
